This invention concerns biologically active 6-keto-8-azaprostanoids and 6-hydroxy-8-azaprostanoids.
There are many references in the literature to prostanoids, a term which is generic to natural and synthetic prostaglandins and prostaglandin-like compounds. It is well known in connection with these prostanoids that even slight differences in chemical structures or stereochemical configurations will have profound effects on biological activity.
Prostanoids have a five-membered ring bearing relatively lengthy substituents on adjacent ring atoms. In most of the known prostanoids, the rings are carbocyclic. Representative of the prostanoids that contain a carbocyclic ring are those described in the following publications: U.S. Pat. No. 4,131,738, U.S. Pat. No. 4,156,092 and U.S. Pat. No. 4,205,178.
In some of the known carbocyclic ring prostanoids, one of the side chains is substituted in the C-16 position by two fluorine atoms. Representative of the publications which disclose carbocyclic-based 16,16-difluoroprostanoids are: Belgium Pat. No. 817,846 (Magerlein), U.S. Pat. No. 4,017,534 (Schaub et al.), U.S. Pat. No. 4,187,381 (Holland et al.), and Magerlein et al., Prostaglandins, 9 (4), 527 to 529 (1975).
U.S. Pat. No. 4,320,136 discloses 8-aza-16,16-difluoroprostanoids that differ from those of the prostanoids of this invention that are 16,16-difluoro-substituted primarily in the character of substituent A.
Other representative heterocycle-based prostanoids are the aza- and diaza-prostanoids disclosed in U.S. Pat. No. 3,873,566 (Scribner), U.S. Pat. No. 3,975,399 (De Franco and Scribner), U.S. Pat. No. 4,003,911 and U.S. Pat. No. 4,032,533 (Scribner), U.S. Pat. No. 4,113,873 (Himizu), U.S. Pat. No. 4,177,346 (Nelson), U.S. Pat. No. 4,211,876 (Scribner), and Belgium Pat. No. 854,268 (Hoechst).
The primary distinction between the prostanoids of this invention and those of the art lies in the character of the substitution (oxo or hydroxy) at the 6-position of an 8-azaprostanoid. This structural feature is believed to enhance the biological properties of the disclosed compounds, for example, as gastric cytoprotective agents that display anti-ulcer activity.